Liver is the primary organ for biotransformation of chemical compounds and their detoxification. Liver injury produced by chemicals has been recognized for over 100 years, and hepatic damage is one of the most common toxicities among drugs at pre-clinical and clinical stages of drug development. Over 30% of new chemical entities (NCE) are generally terminated due to adverse liver effects in humans. During a period of 30 years, hepatotoxicity has been the major cause of drug withdrawal for safety reasons at the marketing stage, accounting for 18% overall drug withdrawal. Many of the drugs that are withdrawn from market due to hepatotoxicity produce lethality in a small percentage of patient population and are classified as type II lesion (or idiosyncratic, sporadic) toxicity.
Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of unrelated chemical compounds that have been used to successfully treat rheumatic and musculospastic disease. Unfortunately, unwanted hepatotoxic side effects have lead to the premature market withdrawal of several NSAIDs, including Cincophen, Benoxaprofen, Piroxicam, Suprofen, and Bromfenac. The pervasiveness of idiosyncratic reactions of many NSAIDs has lead the Food and Drug Administrations Arthritis Advisory Board to conclude that NSAIDs as a group should be considered to induce hepatotoxicity.
It is estimated that annual NSAIDS consumption in the U.S exceeds 10,000 tons. Due to this large consumption of NSAIDS for a wide variety of pain and inflammatory conditions, it has become an important class of drugs responsible for liver injury, despite the overall extremely low incidence of producing hepato-toxicity. Liver injury resulting from NSAIDs can have several forms, including acute toxicity resulting from hepatocellular (parenchymal) damage (e.g. necrosis) and arrested bile flow (cholestasis). The general mechanism that is thought to mediate NSAIDS toxicity is idisyncratic reaction (Type II) to the drug (both immunologic and metabolic), which is dose independent, and presumably results from interindividual variation in drug metabolism. Currently no clear mechanism of drug-induced idiosyncratic toxicity is available. Accordingly, there remains a great need to elucidate the molecular basis of idiosyncratic hepatoxicity, such as NSAID-induced toxicity, including the identification of genes and proteins differentially expressed in response to administration of such drugs.